| Autor: |
Cartlidge, Robert A., Thomas, G. R., Cagnol, Sebastien, Jong, Kimberly A., Molton, Sarah A., Finch, Andrew J., McMahon, Martin |
| Zdroj: |
Pigment Cell Research; October 2008, Vol. 21 Issue: 5 p534-544, 11p |
| Abstrakt: |
Somatic activating mutations of BRAFare the earliest and most common genetic abnormality detected in the genesis of human melanoma. However, the mechanism(s) by which activated BRAFpromotes melanoma cell cycle progression andor survival remain unclear. Here we demonstrate that expression of BIM, a pro-apoptotic member of the BCL-2 family, is inhibited by BRAF?MEK?ERK signaling in mouse and human melanocytes and in human melanoma cells. Trophic factor deprivation of melanocytes leads to elevated BIM expression. However, re-addition of trophic factors or activation of a conditional form of BRAFV600Eleads to rapid inhibition of BIM expression. In both cases, inhibition of BIM expression was dependent on the activity of MEK12 and the proteasome. Consistent with these observations, pharmacological inhibition of BRAFV600Eor MEK12 in human melanoma cells (using PLX4720 and CI-1040 respectively) led to a striking elevation of BIM expression. Re-activation of BRAF?MEK?ERK signaling led to phosphorylation of BIM-EL on serine 69 and its subsequent degradation. Interestingly, endogenous expression of BIM in melanoma cells was insufficient to induce apoptosis unless combined with serum deprivation. Under these circumstances, inhibition of BIM expression by RNA interference provided partial protection from apoptosis. These data suggest that regulation of BIM expression by BRAF?MEK?ERK signaling is one mechanism by which oncogenic BRAFV600Ecan influence the aberrant physiology of melanoma cells. |
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